Mirtazapine disappoints in BETTER-B trial

The investigational antidepressant mirtazapine appears no better than placebo at alleviating severe, intractable breathlessness from chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD), as shown in the phase III BETTER-B trial.

The primary outcome of worst breathlessness over 24 hours was no different between patients treated with mirtazapine and placebo (p=0.69) as measured on the Numerical Rating Scale (NRS 0–10, where 0=no breathlessness and 10=worst breathlessness) after 56 days of treatment. [Lancet Respir Med 2024;doi:10.1016/S2213-2600(24)00187-5]

NRS scores only dropped from a mean of 6.5 to 6.4 in the mirtazapine group compared with 6.3, which remained flat in the placebo group. The pre-set minimal important difference was a between-group difference of 0.55.

Severe breathlessness is common among COPD and ILD patients, with limited therapeutic options. The excitement with mirtazapine in this setting fizzled out with the current findings, which showed no benefit.

Why not mirtazapine

Mirtazapine is an oral tetracyclic antidepressant backed by case reports and a small feasibility study, said study author Irene Higginson, PhD, of Kings College London, UK, at ERS 2024.  

This pointed to “a strong rationale for the study,” commented Dr Kris Mooren of Spaarne Gasthius, Haarlem, the Netherlands, in an accompanying editorial. [Lancet Respir Med 2024; doi:10.1016/S2213-2600(24)00213-3]

“Tricyclic and tetracyclic antidepressants have an anxiolytic effect,” she explained. “Their possible effectiveness is supported by recent studies that underpin the positive role of mood modulation in breathlessness perception.”

She added that it is not uncommon for clinicians to prescribe antidepressants to patients with intractable breathlessness to improve symptoms and mood. “However, only a few case series have examined the use of antidepressants in this setting.”

In the SADHART-CHF study, for example, sertaline, an antidepressant of the selective serotonin reuptake inhibitor class, did not provide a greater reduction in depression or improved cardiovascular status relative to placebo among patients with HF and depression. [J Am Coll Cardiol 2010;56:692-699]

“I think it would make sense to identify patients with breathlessness only, or those triggered on exertion, from emotionally charged breathlessness,” Mooren said. “From our experience working with patients, the first group can often handle their breathlessness provided they receive adequate support. As for the emotionally charged group, breathlessness evokes feelings of terror, despair, or hopelessness. Thinking that a one-dimensional therapy such as a pill would be beneficial is too optimistic.”

Without effective therapy for severe breathlessness, Mooren urged for individualized approaches to care. “This group need resourceful healthcare professionals working in a multidisciplinary manner in breathlessness support services or rehabilitation centres.”

Not your next go-to pill

“We are not recommending mirtazapine for severe breathlessness,” emphasized Higginson. “Using off-label medicines that we can get, because it is imperative that we want to do something, is definitely not advisable.” 

Included in the study were 225 patients (mean age 74 years, 80 percent had comorbidities) with severe breathlessness from COPD or ILD, who were treated with mirtazapine (15 mg, escalating to a maximum of 45 mg) daily or placebo. Fifty-five percent had COPD. Over 20 percent had Hospital Anxiety and Depression Scale (HADS) scores above 10 (suggestive of moderate anxiety/depression). Sixteen percent were already taking opioids.

Acute hospital visits were numerically higher with mirtazapine than placebo (mean 0.99 vs 0.48), and so were outpatient visits (mean 1.66 vs 1.32) and hours of family care (mean 73 vs 58). Adverse events (dry mouth, somnolence, fatigue, and sedation) were also higher with mirtazapine than placebo(64 percent vs 40 percent).